Vital exhaustion, defined as excessive fatigue, demoralization, and irritability due to chronic stress, is independently associated with cardiovascular disease (CVD).The purpose of this study was to examine the association of vital exhaustion with biomarkers associated with CVD risk in the ARIC (Atherosclerosis Risk In Communities) study.We examined the cross-sectional association of vital exhaustion (assessed using the Maastricht Vital Exhaustion Questionnaire [MVEQ]) with cardiac biomarker (high-sensitivity troponin T [hs-TnT], N-terminal pro-B-type natriuretic peptide [NT-proBNP]) and high-sensitivity C-reactive protein (hs-CRP) levels in 11,542 ARIC study participants without CVD at ARIC visit 2 using multivariable logistic and linear regression models. We then analyzed the association of vital exhaustion symptoms in the presence or absence of elevated biomarker levels with incident CVD events (coronary heart disease, ischemic stroke, or heart failure hospitalization) and all-cause mortality over a 10- and 20-year follow-up period using Cox proportional hazard models.Compared with the lowest quartile of vital exhaustion (MVEQ ≤4), the highest quartile (MVEQ 16-42) was associated with elevated hs-TnT, NT-proBNP, and hs-CRP, with ORs of 1.75 (95% CI: 1.34-2.29), 1.40 (95% CI: 1.19-1.64), and 1.14 (95% CI: 1.01-1.28), respectively. The presence of both severe symptoms of vital exhaustion and elevated biomarker levels was associated with greater risk of CVD events and all-cause mortality.In middle-aged adults without CVD, vital exhaustion was associated with elevated hs-TnT, NT-proBNP, and hs-CRP, independent of traditional CVD risk factors. Evaluation of vital exhaustion symptoms and cardiac biomarker levels can help identify individuals at increased risk for incident CVD events and all-cause mortality.